Project Summary Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in men. Given the increasing proportion of the aging population and common application of prostate cancer screening, the incidence of prostate cancer has increased over the last two decades and detection of cancer at early phases is more common. Accumulating evidence from clinical and preclinical studies demonstrates that white button mushroom (WBM) has beneficial effects on prostate cancer. Therefore, we propose a transdisciplinary approach to address Provocative Question 11: Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment? Specifically, we will determine the mechanisms through which consumption of WBM leads to reduction of prostate-specific antigen (PSA) levels in biochemically recurrent prostate cancer (BRPC) patients and those who are therapy nave, favorable risk, and under active surveillance. Our previous Phase 1 study of WBM demonstrated biological activity and a low toxicity profile in BRPC patients. Results showed that 36% of the study population had some decline in PSA levels after ~3 months of WBM treatment and no dose limiting toxicities were observed. Our analysis of trial blood samples suggested potential mechanisms of action; complete response patients had significantly higher levels of IL-15, and most patients exhibited therapy-associated declines in myeloid-derived suppressor cells (MDSCs) after therapy. Our preliminary studies and the work of others further suggest that WBM inhibits arginase activity. Because MDSCs exert an immunosuppressive activity through release of arginase, this suggests a possible mechanism through which WBM may affect immune function. In addition, inhibition of arginase by WBM can lead to decreased polyamine levels, which in turn decreases expression of the androgen receptor (AR) and AR-regulated genes such as PSA, suggesting an additional mechanism through which WBM may act. Based on these findings, we hypothesize that the progression of prostate cancer may be attenuated by inhibiting MDSCs and modulating other immune functions through WBM consumption. We propose three specific aims to test this hypothesis: 1. To examine the PSA suppressing effect of WBM in patients with BRPC and who are therapy nave, favorable risk, and under active surveillance through a Phase 2 clinical trial. 2. To determine the direct and immune-mediated antitumor effects of WBM in blood specimens and biopsy tissue from prostate cancer patients. We will also assess the levels of IL-15 and correlate to WBM response in our proposed Phase 2 trial. 3. To define the cellular and molecular mechanisms underlying WBM effects on the tumor-associated immune cell populations in preclinical syngeneic prostate tumor models, including IL-15 knockout and transgenic mice for determining the effect of IL-15 on WBM-mediated immune modulations. Collectively, we expect the proposed studies to lead to new dietary regimens and other approaches to reduce or mitigate the progression of prostate cancer or improve the efficacy of androgen deprivation therapy.